Background. Pain is the most common presenting somatic symptom in medical outpatients, and depression and anxiety are the two most common mental disorders. All three conditions are often inadequately treated and result in substantial disability, reduced health-related quality of life, and increased health care costs and utilization. Additionally, pain, anxiety, and depression (PAD) are frequently comorbid with one another and have reciprocal negative effects on treatment response and additive effects on adverse health outcomes. The PAD triad is especially burdensome in Veterans, with their high prevalence of chronic pain, depression, PTSD, and other anxiety disorders. Objectives. The Comprehensive vs. Assisted Management of Mood and Physical Symptoms (CAMMPS) study is a randomized comparative effectiveness trial designed to test the relative effectiveness of a lower-resource vs. a higher-resource enhancement of usual primary care in the management of veterans suffering from with pain plus anxiety and/or depression. Research Design. This will be a single-site study enrolling Veterans. Patients followed in primary care clinics at the Roudebush VAMC will be eligible if they have clinically significant levels of pain plus comorbid anxiety and/or depression. A total of 300 eligible patients who provide informed consent will be randomized to one of two treatment arms. One group (n=150) will receive assisted symptom management (ASM) consisting of automated symptom monitoring by interactive voice recording or Internet and prompted pain self-management guided by symptom levels. The second group (n=150) will receive comprehensive symptom management (CSM) which combines ASM with optimized medication management delivered by a nurse-physician specialist team and facilitated mental health care. This team will partner with both VA primary care physicians/PACTs and psychologists embedded in primary care to monitor and adjust treatments using evidence-based analgesic and antidepressant algorithms, reinforced self-management, and care coordination. We postulate that although both interventions are likely to be beneficial, CSM will be superior to ASM. In short, this trial compares: 1) usual care plus assisted symptom management (ASM) vs. 2) usual care plus ASM plus optimized medication and facilitated mental health care (CSM). Outcomes will be assessed at 1, 3, 6, and 12 months. The primary outcome is a composite pain-anxiety- depression severity score. Secondary outcomes include individual pain, anxiety, and depression scores; functional status and health-related quality of life; treatment satisfaction; and perceived barrier and facilitators of the CSM and ASM interventions. The rationale for ASM is preliminary evidence of its effectiveness and its lower use of resources. The rationale for CSM is that the addition of optimized medication management, facilitated mental health care, and coordination with both primary care physicians/PACTS and psychologists for the PAD symptoms should substantially enhance the benefits of ASM. Innovation. CAMMPS provides an integrated approach to PAD symptom comorbidity rather than fragmented care of single symptoms; coordinated symptom management in partnership with both primary care clinicians and psychologists embedded in primary care; the efficient use of health information technology; attention to physical and psychological symptom comorbidity; and the coup- ling of self-management with optimized medication management and facilitated mental health care.